Urea Cycle Activation Triggered by Host–Microbiota Maladaptation Driving Colorectal Tumorigenesis

Maladaptation of host-microbiota metabolic interplay plays a critical role in colorectal cancer initiation. Here, through a combination of single-cell transcriptomic, metagenome, metabonomics, biological and clinical analysis on colorectal adenoma and carcinoma tissues, we demonstrated that host’s urea cycle metabolism is significantly activated during colorectal tumorigenesis, accompanied by the absence of beneficial bacteria with ureolytic capacity, represented by Bifidobacterium, and the overabundant of pathogenic bacteria lack of ureolytic function. Urea could enter into macrophages, inhibit the binding efficiency of p-STAT1 to SAT1 promotor region and further skew macrophages toward pro-tumoral phenotype characterized by accumulation of polyamines. Treating murine model by urea cycle inhibitor or supplemented with probiotics could mitigate the urea-mediated tumorigenesis. Collectively, this study highlighted the utility of urea cycle inhibitor or therapeutically manipulating microbial composition by probiotics to prevent colorectal cancer.Funding Information: This project was supported in part by grants from the State Key R&D Program (2020YFA0509200), National Natural Science Foundation of China (81830081,31970718,81972203, 81421001, 81530072, 81871901, 81874159, 81790632,82073115); the Shanghai Municipal Education Commission— Gaofeng Clinical Medicine Grant (No. 20152512, 20161309); Program of Shanghai Young Academic/Technology Research Leader(19XD1422400); Clinical Research Plan of SHDC (SHDC2020CR1034B), Shanghai Sailing Program (21YF1425600) and Innovative research team of high-level local universities in Shanghai; Shanghai Municipal Health Commission, Collaborative Innovation Cluster Project (2019CXJQ02).Declaration of Interests: Authors declare no competing interests.Ethics Approval Statement: The Ethics Committees of Renji Hospital approved the study protocols (KY2020-092; KY2020-094), and written informed consent was obtained before the investigation. All the research was carried out in accordance with the provisions of the Helsinki Declaration of 1975.All mouse experiments were conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All of the study procedures were approved by the Institutional Animal Care and Use Committee of Renji Hospital, School of Medicine, Renji University.